Extracts of the resin of the guggul tree (Commiphora mukul) lower serum LDL cholesterol and triglyceride levels in animal models and humans. Among a number of compounds present in this extract, the stereoisomers E- and Zgugguisterone (cis- and trans-4,17(20)-pregnadiene-3,16-dione) have been shown to directly decrease LDL cholesterol levels in animal models. Our studies show that this natural plant product, guggulsterone, is a relatively potent, efficacious and specific FXR antagonist. The long-term objectives of this proposal are to understand the mechanism by which gugguisterone lowers serum cholesterol levels and the role of FXR in mediating these effects. Based on the clear role of this receptor in cholesterol metabolism, we hypothesize that FXR plays a major role in mediating the hypolipidemic activity of gugguisterone. To determine whether gugguisterone decreases serum cholesterol levels via the bile acid receptor FXR, the following aims will be pursued: (1) to investigate the hypolipidemic activity of guggulsterone in wild type and FXR null mice; (2) to determine, using a gene array approach, whether FXR is the primary target by which guggulster lowers total serum cholesterol levels. The results from these experiments will determine if FXR is required by guggL rone to lower lipid levels. In addition, these studies will provide insight into the effects of FXR antagonist ligands on total serum cholesterol levels